GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Authors: Remi Stevelink, Ciarán Campbell, Siwei Chen, Bassel Abou-Khalil, Oluyomi M. Adesoji, Zaid Afawi, Elisabetta Amadori, Alison Anderson, Joseph Anderson, Danielle M. Andrade, Grazia Annesi, Pauls Auce, Andreja Avbersek, Melanie Bahlo, Mark D. Baker, Ganna Balagura, Simona Balestrini, Carmen Barba, Karen Barboza, Fabrice Bartolomei, Thomas Bast, Larry Baum, Tobias Baumgartner, Betül Baykan, Nerses Bebek, Albert J. Becker, Felicitas Becker, Caitlin A. Bennett, Bianca Berghuis, Samuel F. Berkovic, Ahmad Beydoun, Claudia Bianchini, Francesca Bisulli, Ilan Blatt, Dheeraj R. Bobbili, Ingo Borggraefe, Christian Bosselmann, Vera Braatz, Jonathan P. Bradfield, Knut Brockmann, Lawrence C. Brody, Russell J. Buono, Robyn M. Busch, Hande Caglayan, Ellen Campbell, Laura Canafoglia, Christina Canavati, Gregory D. Cascino, Barbara Castellotti, Claudia B. Catarino, Gianpiero L. Cavalleri, Felecia Cerrato, Francine Chassoux, Stacey S. Cherny, Ching-Lung Cheung, Krishna Chinthapalli, I-Jun Chou, Seo-Kyung Chung, Claire Churchhouse, Peggy O. Clark, Andrew J. Cole, Alastair Compston, Antonietta Coppola, Mahgenn Cosico, Patrick Cossette, John J. Craig, Caroline Cusick, Mark J. Daly, Lea K. Davis, Gerrit-Jan de Haan, Norman Delanty, Chantal Depondt, Philippe Derambure, Orrin Devinsky, Lidia Di Vito, Dennis J. Dlugos, Viola Doccini, Colin P. Doherty, Hany El-Naggar, Christian E. Elger, Colin A. Ellis, Johan G. Eriksson, Annika Faucon, Yen-Chen A. Feng, Lisa Ferguson, Thomas N. Ferraro, Lorenzo Ferri, Martha Feucht, Mark Fitzgerald, Beata Fonferko-Shadrach, Francesco Fortunato, Silvana Franceschetti, Andre Franke, Jacqueline A. French, Elena Freri, Monica Gagliardi, Antonio Gambardella, Eric B. Geller, Tania Giangregorio, Leif Gjerstad, Tracy Glauser, Ethan Goldberg, Alicia Goldman, Tiziana Granata, David A. Greenberg, Renzo Guerrini, Namrata Gupta, Kevin F. Haas, Hakon Hakonarson, Kerstin Hallmann, Emadeldin Hassanin, Manu Hegde, Erin L. Heinzen, Ingo Helbig, Christian Hengsbach, Henrike O. Heyne, Shinichi Hirose, Edouard Hirsch, Helle Hjalgrim, Daniel P. Howrigan, Donald Hucks, Po-Cheng Hung, Michele Iacomino, Lukas L. Imbach, Yushi Inoue, Atsushi Ishii, Jennifer Jamnadas-Khoda, Lara Jehi, Michael R. Johnson, Reetta Kälviäinen, Yoichiro Kamatani, Moien Kanaan, Masahiro Kanai, Anne-Mari Kantanen, Bülent Kara, Symon M. Kariuki, Dalia Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Mitsuhiro Kato, Josua Kegele, Yeşim Kesim, Nathalie Khoueiry-Zgheib, Chontelle King, Heidi E. Kirsch, Karl M. Klein, Gerhard Kluger, Susanne Knake, Robert C. Knowlton, Bobby P. C. Koeleman, Amos D. Korczyn, Andreas Koupparis, Ioanna Kousiappa, Roland Krause, Martin Krenn, Heinz Krestel, Ilona Krey, Wolfram S. Kunz, Mitja I. Kurki, Gerhard Kurlemann, Ruben Kuzniecky, Patrick Kwan, Angelo Labate, Austin Lacey, Dennis Lal, Zied Landoulsi, Yu-Lung Lau, Stephen Lauxmann, Stephanie L. Leech, Anna-Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Gaetan Lesca, Costin Leu, Naomi Lewin, David Lewis-Smith, Gloria H.-Y. Li, Qingqin S. Li, Laura Licchetta, Kuang-Lin Lin, Dick Lindhout, Tarja Linnankivi, Iscia Lopes-Cendes, Daniel H. Lowenstein, Colin H. T. Lui, Francesca Madia, Sigurdur Magnusson, Anthony G. Marson, Patrick May, Christopher M. McGraw, Davide Mei, James L. Mills, Raffaella Minardi, Nasir Mirza, Rikke S. Møller, Anne M. Molloy, Martino Montomoli, Barbara Mostacci, Lorenzo Muccioli, Hiltrud Muhle, Karen Müller-Schlüter, Imad M. Najm, Wassim Nasreddine, Benjamin M. Neale, Bernd Neubauer, Charles R. J. C. Newton, Markus M. Nöthen, Michael Nothnagel, Peter Nürnberg, Terence J. O’Brien, Yukinori Okada, Elías Ólafsson, Karen L. Oliver, Çiğdem Özkara, Aarno Palotie, Faith Pangilinan, Savvas S. Papacostas, Elena Parrini, Carlos N. Pato, Michele T. Pato, Manuela Pendziwiat, Slavé Petrovski, William O. Pickrell, Rebecca Pinsky, Tommaso Pippucci, Annapurna Poduri, Federica Pondrelli, Rob H. W. Powell, Michael Privitera, Annika Rademacher, Rodney Radtke, Francesca Ragona, Sarah Rau, Mark I. Rees, Brigid M. Regan, Philipp S. Reif, Sylvain Rhelms, Antonella Riva, Felix Rosenow, Philippe Ryvlin, Anni Saarela, Lynette G. Sadleir, Josemir W. Sander, Thomas Sander, Marcello Scala, Theresa Scattergood, Steven C. Schachter, Christoph J. Schankin, Ingrid E. Scheffer, Bettina Schmitz, Susanne Schoch, Susanne Schubert-Bast, Andreas Schulze-Bonhage, Paolo Scudieri, Pak Sham, Beth R. Sheidley, Jerry J. Shih, Graeme J. Sills, Sanjay M. Sisodiya, Michael C. Smith, Philip E. Smith, Anja C. M. Sonsma, Doug Speed, Michael R. Sperling, Hreinn Stefansson, Kári Stefansson, Bernhard J. Steinhoff, Ulrich Stephani, William C. Stewart, Carlotta Stipa, Pasquale Striano, Hans Stroink, Adam Strzelczyk, Rainer Surges, Toshimitsu Suzuki, K. Meng Tan, R. S. Taneja, George A. Tanteles, Erik Taubøll, Liu Lin Thio, G. Neil Thomas, Rhys H. Thomas, Oskari Timonen, Paolo Tinuper, Marian Todaro, Pınar Topaloğlu, Rossana Tozzi, Meng-Han Tsai, Birute Tumiene, Dilsad Turkdogan, Unnur Unnsteinsdóttir, Algirdas Utkus, Priya Vaidiswaran, Luc Valton, Andreas van Baalen, Annalisa Vetro, Eileen P. G. Vining, Frank Visscher, Sophie von Brauchitsch, Randi von Wrede, Ryan G. Wagner, Yvonne G. Weber, Sarah Weckhuysen, Judith Weisenberg, Michael Weller, Peter Widdess-Walsh, Markus Wolff, Stefan Wolking, David Wu, Kazuhiro Yamakawa, Wanling Yang, Zuhal Yapıcı, Emrah Yücesan, Sara Zagaglia, Felix Zahnert, Federico Zara, Wei Zhou, Fritz Zimprich, Gábor Zsurka, Quratulain Zulfiqar Ali
Journal: Nature Genetics (2023)

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.